Cross-reactive Lupus antibodies

SLE is associated with abnormalities of the central nervous system (CNS). Many clinical manifestations of SLE are mediated by autoantibodies, particularly those specific for native DNA. A number of cross-reactive, non-DNA tissue antigens have been identified for anti-DNA antibodies. In particular, the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly binds an anti-DNA antibody. This sequence motif is present in the extracellular domain of murine and human NMDA receptor subunits NR2a and NR2b. In Nature Medicine, DeGiorgio et al show that both human and mouse anti-DNA antibodies recognize the N2R receptor. These cross-reactive antibodies induced apoptosis of neurons in vitro and in vivo and were found in the cerebrospinal fluid of a patient with SLE. Thus, the presence of lupus antibodies that cross-react with NMDA receptors in the cerebrospinal fluid may explain some of the CNS clinical manifestations linked to SLE.

Nat. Medicine 7, 1189–1193 (2001)

GM-CSF key in Multiple Sclerosis

Understanding how inflammatory lesions are initiated and perpetuated in the CNS has remained crucial to development of potential therapeutic agents that may block the demyelinating disease process in MS. In the J. Exp. Med., Bernard and colleagues show the hematopoietic growth factor GM-CSF plays a crucial role in the effector phase of lymphocyte recruitment to the CNS parenchyma and maintenance of inflammatory lesions. Mice deficient for GM-CSF developed fewer clinical symptoms of experimental autoimmune encephalomyelitis (EAE), as compared to WT mice, when immunized with myelin oligodendrocyte glycoprotein. Yet, CD4+ immune responses in these mice, seen by antibody responses in vivo and Con A-stimulated proliferation in vitro, were not abrogated. Importantly, blocking GM-CSF action in vivo ameliorated the disease process in WT mice, even after onset of symptoms. Thus, GM-CSF may pose a potential target for treatment of MS.

J. Exp. Med. 194, 873–881 (2001)

Unfavorable cytotoxic T cells

Plaques of infiltrating CD4+ and CD8+ T cells of unknown function and specificity are found in multiple sclerosis (MS) patients. Research has focused on CD4+ T cells, as EAE induction is CD4+ T cell–dependent, MS susceptibility is associated with MHC class II genes and the TCR sequence motifs found within MS plaques are similar to myelin-specific peripheral CD4+ T cells. In the Journal of Experimental Medicine, Huseby et al. show that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The disease induced by these CD8+ T cells exhibited some clinical signs and CNS pathology not seen in classic EAE mediated by myelin-specific CD4+ T cells. IFN-γ, but not TNF-α or Fas-FasL, interactions played an important role in CD8+ T cells specific for myelin protein. These results now implicate CD8+ myelin-specific CTLs, in addition to CD4+ T cells, as mediators of CNS autoimmunity.

J. Exp. Med. 194, 669–676 (2001)

IFN-inducible genes in Lupus

Multiple genetic traits predispose individuals to systemic lupus erythematosus, an autoimmune disease characterized by production of autoantibodies and glomerulonephritis. In Immunity, Kotzin and colleagues report the identification of Ifi202, an interferon-inducible gene that encodes p202 (a regulator of apoptosis in B cells), as a lupus-susceptibility gene in mice. Gene expression profiling revealed reciprocal differential expression of linked genes Ifi202 and Ifi203. Animals that showed elevated serum antibodies and increases in splenic B cells had increased p202, but not p203, expression. Polymorphisms detected within the Ifi202 promoter correlated with both increased expression, B cell accumulation, apoptosis-resistance and disease susceptibility. These data support the enhancing role of interferon in systemic lupus and identify a target gene for elucidation of the pathways that contribute to this disease.

Immunity 15, 435–443 (2001)

Protective glycolipids

Deficiency in NKT cells may be causal to type 1 diabetes. Vα14+ NKT cells recognize α-galactosylceramide (α-GalCer) glycolipid presented by MHC class I–like molecule CD1d. In Nature Medicine Sharif et al. and Hong et al. and Wang et al. in the Journal of Experimental Medicine analyze the protective effect of α-GalCer treatment on the development of diabetes in NOD mice. Even when initiated after the onset of insulitis, α-GalCer treatment protects NOD mice from type 1 diabetes in a CD1d-dependent manner. Both Sharif et al. and Hong et al. also show protection is correlated with a polarized TH2-like response as well as suppression of islet-specific T and B cell responses. These studies suggest α-GalCer may be useful in the treatment of human type 1 diabetes.

Nature Med. 7, 1052–1056 & 1057–1062 (2001)

J. Exp. Med. 194, 313–319 (2001)

Mimicry or nonspecific stimuli?

The association between viral infections and induction or exacerbation of autoimmune disease is poorly understood. In Immunity, Cantor and colleagues examine the relative roles of molecular mimicry and nonspecific inflammatory stimuli in the transition from infection to autoimmune disease. They use a replication-competent murine herpes virus 1 (HSV-1 KOS) point mutant, which contains a single amino acid exchange in the putative mimicry epitope, and mice expressing a TCR transgene specific for the self-peptide mimic. They show that viral mimicry is critical for disease induction after low-level viral infection of mice containing limited numbers of autoreactive T cells, whereas innate immune mechanisms are sufficient to provoke disease in animals containing expanded numbers of autoreactive T cells. Thus, both viral mimicry and nonspecific innate immune mechanisms have dominant roles in the generation of autoimmunity under particular conditions.

Immunity 15, 137–147 (2001)

Deviating TH1 cells

DNA vaccines can be used to elicit immunity or tolerance. To modulate the immune response to DNA vaccines, preparations that contain cytokine genes and genes to certain pathogens have been used in “covaccines.” In Immunity, Steinman and colleagues show covaccination of mice with a construct encoding IL-4 and residues 139–151 of the self-peptide proteolipid protein, PLP(139–151), protects against experimental autoimmune encephalomyelitis (EAE) induction by PLP(139–151). IL-4–dependent STAT6 phosphorylation induced autoreactive T cells to shift their cytokine profile to TH2. In addition, DNA covaccination with the genes encoding myelin basic protein and IL-4 can reverse established EAE. Thus, this method of protective immunity using DNA vaccination and local gene delivery could prove beneficial in the treatment of multiple sclerosis and other autoimmune diseases caused by TH1 autoreactive cells.

Immunity 15, 15–22 (2001)

Spontaneous autoimmunity

Animal models of autoimmune diseases often require repeated immunizations with self-antigen to recapitulate disease development, frequently without complete penetrance. Shevach and colleagues report in the European Journal of Immunology the development of a mouse model of organ-specific autoimmune disease that occurs spontaneously with complete penetrance in young animals. Mice transgenic for TxA23 (a CD4 TCR), which recognizes the gastric parietal cell protein H/K ATPase α-chain, develop severe autoimmune gastritis that resembles the disease pernicious anemia in humans. Adoptive transfer of 103 lymphocytes conferred severe disease development in immunocompromised hosts, but transfer of 107 cells into wild-type recipients only induced mild gastritis, consistent with the of loss of immunoregulatory cells in immunocompetent hosts. This mouse model should prove insightful for determining the regulatory factors responsible for autoimmune disease development, progression and suppression.

Eur. J. Immunol. 31, 2094–2103 (2001)

Key genes in end-stage arthritis

Arthritis, like many autoimmune diseases, develops in distinct stages that may be influenced by multiple independent disease susceptibility traits. In the Journal of Experimental Medicine, Ji et al. identify the genes that underlie these susceptibilities to discrete phases of arthritic disease in inbred mice. Transfer of serum or immunoglobulin from arthritic animals into healthy recipients can provoke rapid end-stage destructive joint disease with high penetrance in susceptible strains. Using this model and back-crossing disease-prone animals with unaffected animals, Ji et al. were able to identify several genetic loci by that predisposed mice to arthritic disease. Genomic scans of a responder–nonresponder pair (C57BL/6 × NOD) localized the dominant susceptibility locus to the complement C5 gene. Other susceptibility loci resided on murine chr1, coinciding with Sle1 but not fcgr2, chr12 or chr18. The power of genomics, teamed with dissection of disease stages, should provide ample cues to understanding the multifactorial contributions that lead to overt autoimmune disease.

J. Exp. Med. 194, 321–330 (2001)

RAGE in diabetic nephropathy

Nephropathy is a fatal disease complication common to end-phase diabetes. Pathogenesis involves mesangial cell expansion followed by glomerulosclerosis. Although mouse models have been developed that recapitulate the pathology of diabetic islet destruction, no models exist for advanced diabetic kidney disease. In the Journal of Clinical Investigation, Yamamoto et al. describe mice that show kidney pathologies similar to the lesions observed in human diabetic disease. Vascular damage due to prolonged hyperglycemia is thought to involve interactions between advanced glycation end products (AGEs) interacting with their receptor (RAGE) on endothelial cells. Mice expressing the human RAGE receptor in vascular cells crossed with those that develop insulin-dependent diabetes show increased AGE serum concentrations. Subsequent kidney damage—as revealed by glomerular hypertrophy, increased albuminuria and mesangial sclerosis—occurs in the RAGE Tg-diabetic mice, but not those lacking the transgene. Importantly, these symptoms could be prevented by administration of the AGE inhibitor, 2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195). Thus, therapeutic intervention of AGE-RAGE interactions may prove beneficial in human disease.

J. Clin. Invest. 108, 261–268 (2001)